U1-70K and U1A and tau pathogenesis in demented and non-demented individuals with Down syndrome

Document Type

Article

Abstract

INTRODUCTION: Splicing protein mislocalization is associated with tau pathogenesis, but its role in Down syndrome (DS) is under-investigated. METHODS: Spliceosome associations with tau and plaque pathology were examined in frontal cortex from DS with dementia (DSD+) and without dementia (DSD-) using quantitative immunoblotting and immunohistochemistry. RESULTS: U1-70K and U1A levels were downregulated, and hnRNPA2B1, 3Rtau, and 4Rtau were upregulated, whereas SRSF2 and CLK1 were unchanged in DSD+. The number of U1-70K lightly labeled cells was only greater in layer III in DSD+. U1A intensely stained nuclei decreased significantly in layer III in DSD+, whereas those lightly labeled significantly increased in layers III and V-VI in DSD+. U1 mislocalization and tangles appeared in each laminae examined in both DS groups but were significantly greater in DSD+. Mislocalized U1s that co-localized with AT8, and not TauC3, were significantly increased in DSD+. DISCUSSION: U1 splicing proteins play a key role in tau pathogenesis in individuals with DS. HIGHLIGHTS: U1 mislocalization and tangle-like profiles appeared in frontal cortex layer III and V-VI neurons in Down syndrome (DS). Frontal cortex hnRNPA2B1 nuclear morphometric values decreased in layer III in DS with dementia. Frontal cortex SRSF2 and CLK1 nuclear proteins were unchanged in DSD+ and without dementia (DSD-).

Keywords

Down syndrome, U1‐70K, amyloid, dementia, spliceosome, splicing proteins, tau

Medical Subject Headings

Humans; Down Syndrome (pathology, metabolism, complications); tau Proteins (metabolism); Female; Male; Middle Aged; Dementia (metabolism, pathology, complications); Aged; Frontal Lobe (metabolism, pathology); Serine-Arginine Splicing Factors (metabolism); Adult; Heterogeneous-Nuclear Ribonucleoprotein Group A-B (metabolism); Ribonucleoprotein, U1 Small Nuclear (metabolism); Protein-Tyrosine Kinases (metabolism); Protein Serine-Threonine Kinases (metabolism)

Publication Date

8-1-2025

Publication Title

Alzheimer's & dementia : the journal of the Alzheimer's Association

E-ISSN

1552-5279

Volume

21

Issue

8

First Page

e70474

PubMed ID

40762109

Digital Object Identifier (DOI)

10.1002/alz.70474

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